Project Summary/Abstract This project brings together an experienced, integrated project team with complementary expertise to advance a new approach to treating melanomas that cannot cured by surgery and have spread in the body. The project attacks a new target, renalase, an endogenous protein that can function as a survival factor, which becomes overexpressed in melanoma, and plays a role in suppressing the body?s host defense to protect the tumor. Melanoma incidence is the highest of all cancers, and despite significant advances in systemic therapies that prolong survival, the death rate from melanoma has increased by 33.2% from 2003 to 2016. These statistics underscore the urgent need for new therapies. Several lines of data point to renalase as a target for melanoma. Renalase expression is higher in metastatic than in primary tumors in patients and these patients have worse outcomes. Preventing renalase production in cancer cells through siRNA in tissue culture or in mouse melanoma models dramatically decreases tumors. Normal mice lacking the renalase gene, have a normal life expectancy and are resistant to melanoma, further suggesting renalase is a feasible target. Renalase is overexpressed by tumor associated macrophages and facilitates tumor growth through a known cancer signaling pathway, STAT 3. Rabbit antibodies have been generated that can recognize renalase and these antibodies block or reduce melanoma in mouse models. Of high interest, in initial studies using melanoma cell lines resistant to current immunotherapies, our antibodies were effective both as single agents and were synergistic when used in combination with existing immunotherapies. This project is designed to translate these results toward a therapeutic product and specifically to humanize several candidate antibodies and evaluate, characterize and prioritize them preclinically. The project will deliver an innovative lead humanized renalase antibody and back up drugs poised for scale up, further development, including toxicological and pharmacologic evaluation, and ultimately, an IND submission to conduct clinical trials.